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PARA-AMINOSALICYLIC ACID IN TUBERCULOSIS
871 The place for anti-histamine drugs is during the period of investigation and until the desensitisation has reached In many cases a sufficient level to limit the symptoms. of intrinsic allergy, or where the offending allergen cannot be discovered, these drugs are invaluable. The severity of the side reactions in some cases indicates the imperative need for beginning with a small dose and increasing it slowly. This fact must be emphasised, since deaths have been reported following the use of anti-histamine drugs. In these cases it appears that the patient was not sufficiently warned of- the possible side effects and had taken a high dosage from the beginning. The side reactions to antistin appear usually to be of a type which are less troublesome than the disorientation and severe drowsiness commonly found with some other members of this group, but all the anti-histamine drugs are safe if the initial dosage is kept low and the patient is warned. I have found that antistin can be used with good effect in cases where benadryl or other drugs of this group have failed or have caused severe side reactions. Conversely, excellent results may sometimes be obtained with the other anti-histamine drugs when antistin has failed.
Preliminary
Communication
PARA-AMINOSALICYLIC ACID IN TUBERCULOSIS EARLY RESULTS OF CLINICAL TRIALS
series of benzoic- and salicylic-acid derivatives investigated by Lehmann1 in Sweden, paga-aminosalicylic acid (P.A.S.) was found to have the most active bacteriostatic action on the tubercle bacillus and to be relatively non-toxic to animals (except guineapigs). It was then used in human tuberculosis in Sweden by Vallentin,2 in whose opinion the results were " fairly promising." A new method of synthesising this compound was evolved by Mr. D. E..Seymour (director of research, Herts Pharmaceuticals Ltd.) in 1946, and, after further toxicity tests in animals, a sufficient quantity of P.A.S. became available for clinical trials to be started at the Grove Park Hospital in March, 1947. To maintain a blood-level of at least 10 mg. per 100 ml. it was estimated provisionally that each case treated by mouth would require 80-140 g. of P.A.S. every week (we still consider this dosage advisable for parenchymatous lesions), but owing to unavoidable manufacturing difficulties continuity of treatment in such dosage has not always been possible. It was found, however, that small quantities of P.A.S. (1-5-3-0 g. weekly, as a 10% solution in sterile distilled water) had an effect on empyemata, &c., when applied locally to the pleural space ; hence 9 cases have received the drug in this way alone. Two intrathecal injections, each of 0-5 g. in a 5% aqueous solution, were given, together with oral dosage, in our single case of tuberculous meningitis complicating extensive pulmonary disease. No undue disturbance was noted by such methods of medication, except that high dosage of the acid itself given by mouth produced nausea and vomiting ; but this effect has been slight since we have substituted the sodium salt. Up to date, 19 patients in the hospital have received P.A.S. All of these patients have pulmonary tuberculosis but only 6 were given the drug as treatment for their pulmonary lesions ; thus these 6 cases will be referred to as the " pulmonary series."
AMONG
"
.
a
cases
pneumonic, miliary,
fibrotic lesions, but
1.
or
demonstrating infiltration cavity with little infiltration,
Lehmann, J. Lancet, 1946, i, 15;
2.
no case was
Svenska Läkartidn.
2029.
Vallentin, G. Svenska Läkartidn. 1946, 43, 2047.
relief. Side reactions developed in 20 of the 54 cases, but only in 7 were they so severe that the ahtistin had to be
stopped. With all anti-histamine drugs, the patient should be warned of the possibility of side reactions. The initial dose should be kept small and the dosage increased slowly. The first dose and any increases should be given at a time when the patient will not be called on to perform skilled movements depending on acts of judgment-e.g., driving a motor-car. I
am
supplies
indebted to Ciba Laboratories of antistin.
1946, 43,
Ltd., Horsham, for
REFERENCES
Bourquin, J. B. (1946) Schweiz. med. Wschr. 76, 296. Fourneau, E., Bovet, D. (1933) Arch. int. Pharmacodyn. 46, 178. Meier, R., Bucher, K. (1946) Schweiz. med. Wschr. 76, 294. Schindler, O. (1946) Ibid, p. 300.
chosen for P.A.S. treatment unless we had evidence that the disease was active (sputum-positive) and progressive during an observation period of at least two months immediately preceding the start of the drug. -No definite conclusions can be drawn from this small series, but the drug does seem to have had a beneficial effect. Within a few days of the first dose the temperature and erythrocyte-sedimentation rate (E.s.n.) fell sharply, and this improvement was maintained unless the treatment was interrupted, when both temperature and E.s.R. rose towards their former level until a further course was given, when they again fell immediately ; these falls in temperature were not attended by sweating. More slowly-i.e., over a few weeks-there was a fall in the pulse-rate and an increase in weight, vital capacity, and hemoglobin content of the blood. The quantity of sputum rapidly decreased in each case, with a striking reduction in the number of tubercle bacilli present. The morphology of the bacilli also changed ; beading and striation were noted, and acid-fast granules appeared which persisted for a considerable time after ordinary bacilli had disappeared (for record purposes such sputum These responses to was still regarded as " positive "). treatment were accompanied by improvement in the general condition and in the radiological appearances ; particularly striking was the reduction in size of some pulmonary cavities during medication. COMPLICATING LESIONS
,
Renal Tuberculosis.-One woman was treated with by mouth for tuberculosis of the upper pole of her left kidney, confirmed by retrograde pyelography and by finding albumin, pus, blood, and tubercle bacilli in the urine. From the 12th day onwards no further tubercle bacilli appeared in the urine, but pus, blood, and albumin persisted until the llth week when the urine finally became clear. She has had no recurrence of renal signs or symptoms up to date-i.e:, six months P.A.S.
afterwards. .iMMM
negligible
PULMONARY SERIES
We tried to choose without cavity, single
SUMMARY
In 37 of 54 cases of hay-fever, urticaria, vasomotor rhinitis, and other allergic conditions, antistin gave much
p.A.s.
872 no great improvement has been achieved so far in her general condition, but the first fortnight’s administration of P.A.S. by mouth has reduced the frequent diarrhoea to one semi-solid stool daily, besides alleviating the pain. ltlonaldi Dra.ixzage.-Ont; patient, being treated by Monaldi drainage for a large apical cavity, had P.A.S. mucilage instilled daily direct into this cavity and left for eight to twelvehours without suction : the discharge was appreciably diminished, but nothing further can yet
be claimed for the case. 9 patients treated by local Empyemata, &c.-()f instillation of P.A.S. into the pleural cavity for tuberculous empyemata, 3 had open sinuses in the chest wall, another had a bronchoplearal fistula in addition to a sinus, and 1 had a bronchopleural fistula. but no sinus. The results obtained in these cases have been particularly rapid and
striking. The first patient in whom this method was tried had chronic tuberculous empyema with a bronchopleural fistula ; open drainage had been employed for two years before thoracoplasty and the fistula, sinus, and empyema cavity had then remained open for ten months. A 5% suspension of the pure acid in water was inserted into the empyema cavity which was then sealed for three days, and this treatment was repeated a fortnight later. Within a month of the original injection of p. A. p. the chest-wall sinus had healed, the patient’s symptoms of bronchopleural fistula had gone, and by X-ray "examination the pre-existing empyema cavity could no longer be Without seen, nor could pus be detected by needling. further treatment this man has worked at his former occupation for the last four months and his recent film shows no sign of relapse. In another man multiple sinuses have healed, and there is evidence of commencing healing in 2 further similar cases. In the remainder the empyemata have either been obliterated or (in the later cases) are showing a definite tendency towards this end ; in the latest bronchopleural fistula the lung is re-expanding, though the fistula remains patent, and spread in the contralateral lung has been checked. In these empyemata, radiological examination suggests a deviation from the usual mechanism of re-expansion, and a proliferation of deposit (probably fibrinous) on the parietal pleura. In. the ordinary way we would have expected at least 3 of this group to have needed a thoracoplasty for the obliteration of the empyema space, but this operation would probably have been postponed because of multiple time sinuses, empliv,4ema,, contralateral disease, &c. ; saved for the patient must also be taken into account in assessing the value of the drug. Further, even with the small dosage employed, the beneficial effects of have in most cases been P.A.s. on the empyema, &c., accompanied by improvement in the pulmonary lesions ; as yet no patient in this series has shown symptoms of retrogression since p.A.s. was begun as a local application." a
,
"
Ct>?r I;LLTs IO 1’
Time alone can determine the stability of the results far achieved with P.A.8. But we feel justified in the beneficial effects noted in these patients with various tuberculous lesions, and in suggesting that the improvement has seemed to be more rapid than with previous methods of treatment. so
recording
AVe wish to thank Herts Pharmaceuticals Ltd. for the pora-aminosalicylic acid. and its sodium salt, used in these preliminary trials.
T. G. DEMPSEY M.B. N.U.I. Acting Deputy Medical Superintendent. Grove Park Hospital, London.
M. H. LOGO M.D.Aberd. Physician-Superintendent
Medical Societies ROYAL
SOCIETY
OF MEDICINE
Carcinoma of the Breast A’r a meeting of the section of surgery on Dec. 3, with Sir MAX PAGE, the president, in the chair, a discussion on the treatment of carcinoma of the breast was opened by Sir GORDON GoRDON-TATLOR. Tracing the evolution of treatment, he paid special tribute to pioneer workers at Middlesex Hospital, including Charles Moore, Sir Alfred Pearce Gould, and W. Sampson Handley. Sir Gordon’s own surgery of mammary cancer has been largely modelled on tha,t of Handley ; but he has not followed Handley in the employment of radium at the time of operation or in the use of postoperative radiation. On over a dozen occasions he has deliberatelv removed the chain of anterior mediastinal glands along with the internal mammary vessels after resection of the 2nd and 3rd costal cartilages ; in retrospect he regrets that he has not more often performed this manoeuvre.
Confidence in preoperative and postoperative irradiation must tend to curtail the extent of surgical ablation. In 1938 four different procedures prevailed among 72 radisurgeons throughout Britain : (1) 25 cal operation without irradiation ;-, (2) 44 % employed irradiation as a supplement to radical operation ; (3) 29 % used irradiation after radical operation in group 2 cases only ; and (4) 2 % favoured irradiation with or without a local operation. Since 1938 the exigencies of war have thrust much of the treatment on to radiotherapeutic clinics. Sir Gordon eschews postoperative radiation for cases in groups. 1 and 2 ; " For such I have preferred a sharp knife, a stout heart, and unquenchable optimism." He was emphatic, however, that when the condition has advanced beyond stage 2, and for treatment of supraclavicular glands and bone metastases, radiation is the method of choice. Even among those who advocate routine ancillary radiotherapy there is no unanimity Stuart Harrington found as to indications or method. that, whether there was axillary-gland involvement difference in the or not, there was no 10-year survival-rate between those receiving radiotherapy and those who did not receive it. Truscott concluded that between 1926 and 1935 treatment was best when surgery alone was employed, and that from 1935 onwards the evidence was insufficient to say whether the combination of radiotherapy with surgery is better than surgery alone. Few papers dealing with radiation refer to the morbidity from this treatment. Apart from unhappy local effects, sickness and other untoward sequelae may lower resistance to any malignant cells remaining after operation. Recurrence has taken place as long as 32 years after operation ; in some no causal factor, except perhaps age, can be impugned as fostering the recrudescence ; but in others recurrence appears to have been preceded by intercurrent disease or by surgical operation for some independent condition. Sir Gordon has seen a recurrence in the scar 17 years after a radical mastectomy and a few weeks after a severe attack of acute pyelonephritis ; he has also seen recurrence in the scar follow an operation for haemorrhoids performed 16 years after the initial amputation. In three cases recurrence manifested itself shortly after a gall-stone operation, while in another patient recurrence seemed to be related to a "herniorCancer rhaphy performed under local anaesthesia. imnumity," after being broken down, seems sometimes to be restored, and Sir Gordon has seen patients survive recurrence for as long as 10 years. The vagaries of this " immunity " or resistance " are seen in alternating efflorescence and retrogression or disappearance of cutaneous nodules and even of invaded lymph-glands ; while preternaturally slow growth of a mammary tumour and the protracted absence of metastases are indicative Still more amazing is of the same cancer resistance. the disappearance of a cancerous mammary growth and its secondaries. Investigation has shown that the average natural duration of untreated cases of mammary cancer is about 31/2 Treatment should, therefore, be gauged by the years.
%undertook
appreciable
"
Preliminary
Communication
PARA-AMINOSALICYLIC ACID IN TUBERCULOSIS EARLY RESULTS OF CLINICAL TRIALS
series of benzoic- and salicylic-acid derivatives investigated by Lehmann1 in Sweden, paga-aminosalicylic acid (P.A.S.) was found to have the most active bacteriostatic action on the tubercle bacillus and to be relatively non-toxic to animals (except guineapigs). It was then used in human tuberculosis in Sweden by Vallentin,2 in whose opinion the results were " fairly promising." A new method of synthesising this compound was evolved by Mr. D. E..Seymour (director of research, Herts Pharmaceuticals Ltd.) in 1946, and, after further toxicity tests in animals, a sufficient quantity of P.A.S. became available for clinical trials to be started at the Grove Park Hospital in March, 1947. To maintain a blood-level of at least 10 mg. per 100 ml. it was estimated provisionally that each case treated by mouth would require 80-140 g. of P.A.S. every week (we still consider this dosage advisable for parenchymatous lesions), but owing to unavoidable manufacturing difficulties continuity of treatment in such dosage has not always been possible. It was found, however, that small quantities of P.A.S. (1-5-3-0 g. weekly, as a 10% solution in sterile distilled water) had an effect on empyemata, &c., when applied locally to the pleural space ; hence 9 cases have received the drug in this way alone. Two intrathecal injections, each of 0-5 g. in a 5% aqueous solution, were given, together with oral dosage, in our single case of tuberculous meningitis complicating extensive pulmonary disease. No undue disturbance was noted by such methods of medication, except that high dosage of the acid itself given by mouth produced nausea and vomiting ; but this effect has been slight since we have substituted the sodium salt. Up to date, 19 patients in the hospital have received P.A.S. All of these patients have pulmonary tuberculosis but only 6 were given the drug as treatment for their pulmonary lesions ; thus these 6 cases will be referred to as the " pulmonary series."
AMONG
"
.
a
cases
pneumonic, miliary,
fibrotic lesions, but
1.
or
demonstrating infiltration cavity with little infiltration,
Lehmann, J. Lancet, 1946, i, 15;
2.
no case was
Svenska Läkartidn.
2029.
Vallentin, G. Svenska Läkartidn. 1946, 43, 2047.
relief. Side reactions developed in 20 of the 54 cases, but only in 7 were they so severe that the ahtistin had to be
stopped. With all anti-histamine drugs, the patient should be warned of the possibility of side reactions. The initial dose should be kept small and the dosage increased slowly. The first dose and any increases should be given at a time when the patient will not be called on to perform skilled movements depending on acts of judgment-e.g., driving a motor-car. I
am
supplies
indebted to Ciba Laboratories of antistin.
1946, 43,
Ltd., Horsham, for
REFERENCES
Bourquin, J. B. (1946) Schweiz. med. Wschr. 76, 296. Fourneau, E., Bovet, D. (1933) Arch. int. Pharmacodyn. 46, 178. Meier, R., Bucher, K. (1946) Schweiz. med. Wschr. 76, 294. Schindler, O. (1946) Ibid, p. 300.
chosen for P.A.S. treatment unless we had evidence that the disease was active (sputum-positive) and progressive during an observation period of at least two months immediately preceding the start of the drug. -No definite conclusions can be drawn from this small series, but the drug does seem to have had a beneficial effect. Within a few days of the first dose the temperature and erythrocyte-sedimentation rate (E.s.n.) fell sharply, and this improvement was maintained unless the treatment was interrupted, when both temperature and E.s.R. rose towards their former level until a further course was given, when they again fell immediately ; these falls in temperature were not attended by sweating. More slowly-i.e., over a few weeks-there was a fall in the pulse-rate and an increase in weight, vital capacity, and hemoglobin content of the blood. The quantity of sputum rapidly decreased in each case, with a striking reduction in the number of tubercle bacilli present. The morphology of the bacilli also changed ; beading and striation were noted, and acid-fast granules appeared which persisted for a considerable time after ordinary bacilli had disappeared (for record purposes such sputum These responses to was still regarded as " positive "). treatment were accompanied by improvement in the general condition and in the radiological appearances ; particularly striking was the reduction in size of some pulmonary cavities during medication. COMPLICATING LESIONS
,
Renal Tuberculosis.-One woman was treated with by mouth for tuberculosis of the upper pole of her left kidney, confirmed by retrograde pyelography and by finding albumin, pus, blood, and tubercle bacilli in the urine. From the 12th day onwards no further tubercle bacilli appeared in the urine, but pus, blood, and albumin persisted until the llth week when the urine finally became clear. She has had no recurrence of renal signs or symptoms up to date-i.e:, six months P.A.S.
afterwards. .iMMM
negligible
PULMONARY SERIES
We tried to choose without cavity, single
SUMMARY
In 37 of 54 cases of hay-fever, urticaria, vasomotor rhinitis, and other allergic conditions, antistin gave much
p.A.s.
872 no great improvement has been achieved so far in her general condition, but the first fortnight’s administration of P.A.S. by mouth has reduced the frequent diarrhoea to one semi-solid stool daily, besides alleviating the pain. ltlonaldi Dra.ixzage.-Ont; patient, being treated by Monaldi drainage for a large apical cavity, had P.A.S. mucilage instilled daily direct into this cavity and left for eight to twelvehours without suction : the discharge was appreciably diminished, but nothing further can yet
be claimed for the case. 9 patients treated by local Empyemata, &c.-()f instillation of P.A.S. into the pleural cavity for tuberculous empyemata, 3 had open sinuses in the chest wall, another had a bronchoplearal fistula in addition to a sinus, and 1 had a bronchopleural fistula. but no sinus. The results obtained in these cases have been particularly rapid and
striking. The first patient in whom this method was tried had chronic tuberculous empyema with a bronchopleural fistula ; open drainage had been employed for two years before thoracoplasty and the fistula, sinus, and empyema cavity had then remained open for ten months. A 5% suspension of the pure acid in water was inserted into the empyema cavity which was then sealed for three days, and this treatment was repeated a fortnight later. Within a month of the original injection of p. A. p. the chest-wall sinus had healed, the patient’s symptoms of bronchopleural fistula had gone, and by X-ray "examination the pre-existing empyema cavity could no longer be Without seen, nor could pus be detected by needling. further treatment this man has worked at his former occupation for the last four months and his recent film shows no sign of relapse. In another man multiple sinuses have healed, and there is evidence of commencing healing in 2 further similar cases. In the remainder the empyemata have either been obliterated or (in the later cases) are showing a definite tendency towards this end ; in the latest bronchopleural fistula the lung is re-expanding, though the fistula remains patent, and spread in the contralateral lung has been checked. In these empyemata, radiological examination suggests a deviation from the usual mechanism of re-expansion, and a proliferation of deposit (probably fibrinous) on the parietal pleura. In. the ordinary way we would have expected at least 3 of this group to have needed a thoracoplasty for the obliteration of the empyema space, but this operation would probably have been postponed because of multiple time sinuses, empliv,4ema,, contralateral disease, &c. ; saved for the patient must also be taken into account in assessing the value of the drug. Further, even with the small dosage employed, the beneficial effects of have in most cases been P.A.s. on the empyema, &c., accompanied by improvement in the pulmonary lesions ; as yet no patient in this series has shown symptoms of retrogression since p.A.s. was begun as a local application." a
,
"
Ct>?r I;LLTs IO 1’
Time alone can determine the stability of the results far achieved with P.A.8. But we feel justified in the beneficial effects noted in these patients with various tuberculous lesions, and in suggesting that the improvement has seemed to be more rapid than with previous methods of treatment. so
recording
AVe wish to thank Herts Pharmaceuticals Ltd. for the pora-aminosalicylic acid. and its sodium salt, used in these preliminary trials.
T. G. DEMPSEY M.B. N.U.I. Acting Deputy Medical Superintendent. Grove Park Hospital, London.
M. H. LOGO M.D.Aberd. Physician-Superintendent
Medical Societies ROYAL
SOCIETY
OF MEDICINE
Carcinoma of the Breast A’r a meeting of the section of surgery on Dec. 3, with Sir MAX PAGE, the president, in the chair, a discussion on the treatment of carcinoma of the breast was opened by Sir GORDON GoRDON-TATLOR. Tracing the evolution of treatment, he paid special tribute to pioneer workers at Middlesex Hospital, including Charles Moore, Sir Alfred Pearce Gould, and W. Sampson Handley. Sir Gordon’s own surgery of mammary cancer has been largely modelled on tha,t of Handley ; but he has not followed Handley in the employment of radium at the time of operation or in the use of postoperative radiation. On over a dozen occasions he has deliberatelv removed the chain of anterior mediastinal glands along with the internal mammary vessels after resection of the 2nd and 3rd costal cartilages ; in retrospect he regrets that he has not more often performed this manoeuvre.
Confidence in preoperative and postoperative irradiation must tend to curtail the extent of surgical ablation. In 1938 four different procedures prevailed among 72 radisurgeons throughout Britain : (1) 25 cal operation without irradiation ;-, (2) 44 % employed irradiation as a supplement to radical operation ; (3) 29 % used irradiation after radical operation in group 2 cases only ; and (4) 2 % favoured irradiation with or without a local operation. Since 1938 the exigencies of war have thrust much of the treatment on to radiotherapeutic clinics. Sir Gordon eschews postoperative radiation for cases in groups. 1 and 2 ; " For such I have preferred a sharp knife, a stout heart, and unquenchable optimism." He was emphatic, however, that when the condition has advanced beyond stage 2, and for treatment of supraclavicular glands and bone metastases, radiation is the method of choice. Even among those who advocate routine ancillary radiotherapy there is no unanimity Stuart Harrington found as to indications or method. that, whether there was axillary-gland involvement difference in the or not, there was no 10-year survival-rate between those receiving radiotherapy and those who did not receive it. Truscott concluded that between 1926 and 1935 treatment was best when surgery alone was employed, and that from 1935 onwards the evidence was insufficient to say whether the combination of radiotherapy with surgery is better than surgery alone. Few papers dealing with radiation refer to the morbidity from this treatment. Apart from unhappy local effects, sickness and other untoward sequelae may lower resistance to any malignant cells remaining after operation. Recurrence has taken place as long as 32 years after operation ; in some no causal factor, except perhaps age, can be impugned as fostering the recrudescence ; but in others recurrence appears to have been preceded by intercurrent disease or by surgical operation for some independent condition. Sir Gordon has seen a recurrence in the scar 17 years after a radical mastectomy and a few weeks after a severe attack of acute pyelonephritis ; he has also seen recurrence in the scar follow an operation for haemorrhoids performed 16 years after the initial amputation. In three cases recurrence manifested itself shortly after a gall-stone operation, while in another patient recurrence seemed to be related to a "herniorCancer rhaphy performed under local anaesthesia. imnumity," after being broken down, seems sometimes to be restored, and Sir Gordon has seen patients survive recurrence for as long as 10 years. The vagaries of this " immunity " or resistance " are seen in alternating efflorescence and retrogression or disappearance of cutaneous nodules and even of invaded lymph-glands ; while preternaturally slow growth of a mammary tumour and the protracted absence of metastases are indicative Still more amazing is of the same cancer resistance. the disappearance of a cancerous mammary growth and its secondaries. Investigation has shown that the average natural duration of untreated cases of mammary cancer is about 31/2 Treatment should, therefore, be gauged by the years.
%undertook
appreciable
"